Detection method of (3R, 4R)-1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride and isomer thereof

A technology of dimethylpiperidine and amine dihydrochloride, which is applied in the field of analytical chemistry, can solve problems that are difficult to achieve, and achieve the effect of ensuring product quality and patient drug safety

Active Publication Date: 2021-01-12
JIANGSU JINGLIXIN PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Under the prior art, two diastereoisomers of 1-benzyl-N,4-dimethylpiperidin-3-amine dihydrochloride RS and SR and RR can be realized under conventional reversed-phase chromatographic conditions. Separation of configuration, but SS configuration and RR configuration are a pair of enantiomers, they have the same physical properties, thermodynamic properties and chemical properties, only show differences in chiral environment, conventional reverse phase It is difficult to separate 1-benzyl-N,4-dimethylpiperidin-3-amine dihydrochloride with SS configuration and RR configuration under chromatographic conditions

Method used

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  • Detection method of (3R, 4R)-1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride and isomer thereof
  • Detection method of (3R, 4R)-1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride and isomer thereof
  • Detection method of (3R, 4R)-1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride and isomer thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1 Conventional HPLC chiral column for the separation of SM-B and its enantiomers

Embodiment 2

[0045] The investigation of embodiment 2 different chiral derivatization reagents

[0046] Test Example 1: Using (S)-(+)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride as derivatization reagent

[0047] Experimental equipment: Aglent 1260 high performance liquid chromatography.

[0048] Chromatographic conditions: the chromatographic column is Welch Ultimate XB-C18 (4.6*250mm, 5μm); the column temperature is 40°C; the ultraviolet detector is used, and the detection wavelength is 210nm; Potassium dihydrogen buffer solution (pH3.0)-methanol (50:50) was used as the mobile phase, and was collected isocratically for 60 minutes.

[0049] Experimental steps:

[0050] 0.1% triethylamine solution: take 100 μl of triethylamine, dilute to 100ml with acetonitrile, and shake well to obtain.

[0051] Derivatization reagent diluent: take 10 mg of (S)-(+)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride, dilute to 10 ml with acetonitrile, and shake well to obtain.

[0052] SM-B enan...

Embodiment 3

[0073] Embodiment 3 The screening of detection method mobile phase of the present invention

[0074] Test Example 1: Screening of mobile phase A pH value

[0075] The purpose of the experiment: choose 0.01mol / L potassium dihydrogen phosphate aqueous solution as the water phase, adjust different pH values, investigate the influence of mobile phase pH value on the detection of SM-B enantiomers, and select appropriate conditions for SM-B Enantiomer detection.

[0076] Experimental equipment: Shimadzu LC-20AT high performance liquid chromatography.

[0077] Chromatographic conditions: the chromatographic column is Welch Ultimate XB-C18 (4.6*250mm, 5μm); the column temperature is 40°C; the ultraviolet detector is used, and the detection wavelength is 210nm; Potassium dihydrogen buffer solution was mobile phase A, adjusted to three different pH values ​​(respectively pH2.3, pH3.0, pH6.0), and mobile phase A-methanol (50:50) was used for isocratic collection for 60 min.

[0078] E...

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Abstract

The invention discloses a detection method of (3R, 4R)-1-benzyl-N, 4-dimethyl piperidine-3-amine dihydrochloride and an enantiomer thereof, which comprises the following steps: carrying out pre-columnderivatization on 1-benzyl-N, 4-dimethyl piperidine-3-amine dihydrochloride by using a chiral derivatization reagent isothiocyanate or isocyanate, and detecting by using high performance liquid chromatography. According to the method, (3R, 4R)-1-benzyl-N, 4-dimethyl piperidine-3-amine dihydrochloride and (3S, 4S)-1-benzyl-N, 4-dimethyl piperidine-3-amine dihydrochloride are separated, the detection cost is low, and the sensitivity, specificity and accuracy are good, so that the method is an effective detection method for controlling the quality of the tofacitinib citrate starting raw material, therefore, the tofacitinib citrate product quality and the medication safety of patients are further ensured.

Description

technical field [0001] The invention belongs to the field of analytical chemistry, in particular to a starting material of tofacitinib citrate (3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine dihydrochloride ( Named SM-B) and its enantiomer detection method. Background technique [0002] Tofacitinib citrate was developed by Pfizer of the United States for the treatment of moderate to severe rheumatoid arthritis (RA) patients who are active in adults and who do not respond well to methotrexate (MTX). [0003] The Chinese chemical name of tofacitinib citrate is (3R,4R)-4-methyl-3-(methyl-1H-pyrrolo[2,3-d]pyrimidine-4-amino)-β-oxo -1-piperidinepropionitrile, 2-hydroxy-1,2,3-propanetricarboxylic acid (1:1), molecular formula C 16 h 20 N 6 O·C 6 h 8 o 7 , the structural formula is: [0004] [0005] There are two chiral centers in the molecule of tofacitinib citrate, and there are four optical isomers: RR, RS, SR, and SS, and the RR configuration is an effective JAK-1 an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N30/02G01N30/06
CPCG01N30/02G01N30/06G01N2030/067
Inventor 沈卫阳朱冬梅张雨佳朱雄
Owner JIANGSU JINGLIXIN PHARMA TECH CO LTD
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